Marijuana (Cannabis sativa L.) and its derivatives have been used for centuries for medicinal and recreational purposes. A major active ingredient in marijuana and hashish has been determined to be Δ9-tetrahydrocannabinol (Δ9-THC). Detailed research has revealed that the biological action of Δ9-THC and other members of the cannabinoid family occurs through two G-protein coupled receptors termed CB1 and CB2. The CB1 receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs. The CB2 receptor is found primarily in lymphoid tissues and cells. Three endogenous ligands for the cannabinoid receptors derived from arachidonic acid have been identified (anandamide, 2-arachidonoyl glycerol, and 2-arachidonyl glycerol ether). Each is an agonist with activities similar to Δ9-THC, including sedation, hypothermia, intestinal immobility, antinociception, analgesia, catalepsy, anti-emesis, and appetite stimulation.
The genes for the respective cannabinoid receptors have each been disrupted in mice. The CB1-/- receptor knockout mice appeared normal and fertile. They were resistant to the effects of Δ9-THC and demonstrated a strong reduction in the reinforcing properties of morphine and the severity of withdrawal syndrome. They also demonstrated reduced motor activity and hypoalgesia. The CB2-/- receptor knockout mice were also healthy and fertile. They were not resistant to the central nervous system mediated effects of administered Δ9-THC. There were some effects on immune cell activation, reinforcing the role for the CB2 receptor in immune system functions.
Excessive exposure to Δ9-THC can lead to overeating, psychosis, hypothermia, memory loss, and sedation. Specific synthetic ligands for the cannabinoid receptors have been developed and have aided in the characterization of the cannabinoid receptors: CP55,940 (J. Pharmacol. Exp. Ther. 1988, 247, 1046-1051); WIN55212-2 (J. Pharmacol. Exp. Ther. 1993, 264, 1352-1363); SR141716A (FEBS Lett. 1994, 350, 240-244; Life Sci. 1995, 56, 1941-1947); and SR144528 (J. Pharmacol. Exp. Ther. 1999, 288, 582-589). The pharmacology and therapeutic potential for cannabinoid receptor ligands has been reviewed (Exp. Opin. Ther. Patents 1998, 8, 301-313; Ann. Rep. Med. Chem., A. Doherty, Ed.; Academic Press, NY 1999, Vol. 34, 199-208; Exp. Opin. Ther. Patents 2000, 10, 1529-1538; Trends in Pharma. Sci. 2000, 21, 218-224). There is at least one CB1 modulator characterized as an inverse agonist or an antagonist, N-(1-piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A), in clinical trials for treatment of eating disorders at this time. There still remains a need for potent low molecular weight CB1 modulators that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.
Treatment of asthma with CB1 receptor modulators (such as CB1 inverse agonists) is supported by the finding that presynaptic cannabinoid CB1 receptors mediate the inhibition of noradrenaline release (in the guinea pig lung) (Europ. J. of Pharmacology, 2001, 431 (2), 237-244).
Treatment of cirrhosis of the liver with CB1 receptor modulators is supported by the finding that a CB1 receptor modulator will reverse the low blood pressure observed in rats with carbon tetrachloride-induced liver cirrhosis and will lower the elevated mesenteric blood flow and portal vein pressure (Nature Medicine, 2001, 7 (7), 827-832).
U.S. Pat. Nos. 5,624,941 and 6,028,084, PCT Application Nos. WO98/43636, WO98/43635, and WO 02/076945, and EPO Application No. EP-658546 disclose substituted pyrazoles having activity against the cannabinoid receptors.
PCT Application Nos. WO98/31227 and WO98/41519 also disclose substituted pyrazoles having activity against the cannabinoid receptors.
PCT Application Nos. WO98/37061, WO00/10967, and WO00/10968 disclose diaryl ether sulfonamides having activity against the cannabinoid receptors.
PCT Application Nos. WO97/29079 and WO99/02499 disclose alkoxy-isoindolones and alkoxyquinolones as having activity against the cannabinoid receptors.
U.S. Pat. No. 5,532,237 discloses N-benzoyl-indole derivatives having activity against the cannabinoid receptors.
U.S. Pat. Nos. 4,973,587, 5,013,837, 5,081,122, and 5,112,820, 5,292,736 disclose aminoalkylindole derivatives as having activity against the cannabinoid receptors.
PCT publication WO 01/58869 discloses pyrazoles, pyrroles and imidazole cannabinoid receptor modulators useful for treating respiratory and non-respiratory leukocyte activation-associated disorders.
PCT publications WO 01/64632, 01/64633, and 01/64634 assigned to Aventis are directed to azetidine derivatives as cannabinoid antagonists.
WO 92/01675 and U.S. Pat. No. 5,492,915 disclose leukotriene B4 antagonists of structural formula:
and in particular discloses ethyl 6-[(5,6-diphenyl-2-pyridyl)oxy]hexanoate, methyl 6-[(5,6-diphenyl-2-pyridyl)oxy]-2,2-dimethylhexanoate, ethyl 8-[(5,6-diphenyl-2-pyridyl)oxy]octanoate, 6-[5,6-diphenyl-2-pyridy)oxy]hexanoic acid, 6-[(5,6-diphenyl-2-pyridyl)oxy]-2,2-dimethylhexanoic acid, and sodium 8-[(5,6-diphenyl-2-pyridyl)oxy]octanoate.
WO 92/02513 discloses heterocyclic compounds of structural formula:
wherein R1 and R2 are each lower alkoxy, useful as antithromotic agents inhibiting cyclooxygenase, thrombin, phosphodiesterase and the like; and in particular, 6-ethyoxycarbonyl-2,3-bis(4-methoxyphenyl)pyridine, 6-acetylaminomethyl-2,3-bis-(4-methoxypheynl)pyridine, 6-(pyridine-4-yl)-2,3-bis(4-methoxyphenyl)pyridine, 2,3-bis(4-methoxyphenyl)-6-(N,N-dimethylaminomethyl)-pyridine, 2,3-bis(4-methoxyphenyl)-6-[(4-methyl-piperazin-1-yl)carbonyl]pyridine dihydrochloride, 2,3-bis(4-methoxyphenyl)-6-[[2-(N,N-dimethylamiono)-ethyl]carbamoyl]pyridine dihydorochloride, 2,3-bis(4-methoxyphenyl)-6-[(4-benzylpiperazin-1-yl)-carbamoyl]pyridine, 6-hydroxymethyl-2,3-bis(4-methoxyphenyl)pyridine, 2,3-bis(4-methoxyphenyl)-6-pyridinecarbaldehyde, 3-[2,3-bis(4-methoxyphenyl)pyridin-6-yl]-(E)-propenoic acid, 3-[2,3-bis(4-methoxyphenyl)pyridine-6-yl]propanoic acid, 6-aminomethyl-2,3-bis(4-methoxyphenyl)pyridine dihydrochloride, 2,3-bis(4-methoxyphenyl)-6-[(3-oxo-2,3,4,5-tetrahdyropyridazin-6-yl)-carbonylaminomethyl]pyridine, 2,3-bis(4-methoxyphenyl)-6-[2-[(3-oxo-2,3,4,5-tetrazhdyropyridazin-6-zy)carbonylamino]ethyl]pyridine, 6-(3-isopropylureidomethyl)-2,3-bis(4-methoxypenyl)-pyridine, 6-(2-aminoethyl)-2,3-bis(4-methoxyphenyl)pyridine, and 2,3-bis(4-methoxyphenyl-6-(N,N-dimethylaminomethyl)-pyridine dihydrochloride.
WO 96/24584 discloses for the treatment of inflammation 2,3-substituted pyridines of structural formula:
provided one of R5 and R6 is substituted with alkylsulfonyl, aminosulfonyl, or haloalkylsulfonyl. WO 00/38786, WO 00/38730, WO 00/38716. WO 00/37107, U.S. Pat. No. 5,916,905, U.S. Pat. No. 5,686,470, WO 98/47509; WO 98/16227, WO 96/41645, WO 96/41625, U.S. Pat. No. 5,700,816, WO 96/41626, U.S. Pat. No. 5,686,470, describe similar compounds as COX-2 inhibitors. WO 99/59635, U.S. Pat. No. 5,861,419, U.S. Pat. No. 6,001,843, WO 98/03484, to Merck & Co., Inc. or Merck Frosst Canada Inc. also disclose 2,3-diphenyl substituted pyridine COX-2 inhibitors, having alkylsulfonyl and aminosulfonyl subsitutuents on the 3-phenyl ring.
U.S. Pat. No. 4,011,328 and UK Patent 1,395,110 are directed to compounds of structural formula:
wherein R1 is hydrogen, halogen C1-6 alkyl, C1-6 alkoxy, and C1-6 alkylthio, A taken separately is H and B is a monosubstitued or unsubstituted phenyl moiety substituted with hydrogen, halogen or C1-6 alkoxy, or A and B taken together form a radical —O—CH2—. These compounds are reported to have analgesic and antiinflammatory properties.
U.S. Pat. No. 4,533,666 is directed to 1,2,6-triaryl pyridine derivatives useful in treating pain, fever, thrombosis, inflammation and arthritis of structural formula:
wherein R is hydrogen, trifluoromethyl, fluoro, chloro, bromo or iodo.
U.S. Pat. Nos. 5,593,994 and 5,932,586 are directed to prostaglandin synthase inhibitors of structural formula:
wherein J, K and L are independently CR3, CR4 or N; R2 is p-methylsulfonyl or p-aminosulfonyl substituted phenyl, 3-pyridyl or 2-pyridyl; X is a single bond (i.e., is absent, or is various linkers; Z is O or S; R1 is optionally substituted phenyl, optionally substituted 2-naphthyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or an optionally substituted heterocyclic ring system.
WO 97/04778 and U.S. Pat. Nos. 5,672,609 and 5,750,708 are directed compounds useful to the treatment of post menopausal symptoms such as osteoporosis, cardiovascular conditions including hyperlipidaemia and the like of structural formula:
wherein n is 2 or 3,; R is dimethyl amino, diethylamino, 1-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, or 1-hexamethyleneimino; R1 is hydrogen, loweralkyl, optionally substituted phenyl, or optionally substituted benzoyloxy; and R2 is hydrogen, hydroxyl, loweralkoxy, benzyloxy, loweralkanoyloxy, optionally substituted benzoyloxy.
EP 0 308 020 is directed to 5,6-disubstitued 1-2-dihydro-2-oxo-3-pyridine carboxylic acids of structural formula:
and their use for treating bacterial infections.
U.S. Pat. No. 6,127,386 is directed to 3-pyridloxymethyl heterocyclic ether compounds that are ligands at neuronal nicotinic cholinergic channel receptors of structural formula:
wherein n is 1, 2, or 3; R2 is hydrogen, lower alkyl, fluorine, chlorine, ethenyl or phenyl; L is a linking group which is present or absent, and R3 is selected from hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, amino, alkylamino, azacyclo, dialkylamino, phenyl, naphthyl, biphenyl, and heterocycles, optionally substituted.
U.S. Pat. No. 5,077,142 is directed to an electroluminescent device comprising a cathod and one or a plurality of organic compound layers sandwiched therebetween which organic compound layers comprise an organic compound which included phenyl-substituted pyridine compounds.
U.S. Pat. No. 4,169,951 is directed to a process for making pyridine compounds substituted in the 2-and 3-positions by aromatic or heteroaromatic groups, including 2,3-diphenyl-6-methyl pyridine,
U.S. Pat. No. 4,006,149 is directed to processes for catalytic production of pyridines from alkynes and nitriles.
UK Patent 1,401,038 discloses the use of 2,4,6-triphenyl pyridine, pentaphenylpyridine, 2,3,5,6-tetraphenyl pyridine, 2-methyl-5-ethyl pyridine, 2,6-dichloropyridine and mixtures of methyl pyridines as chlorination catalysts.
The compounds of the present invention are modulators of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the Cannabinoid-1 (CB1) receptor. In particular, compounds of the present invention are antagonists or inverse agonists of the CB1 receptor. The invention is concerned with the use of these compounds to modulate the Cannabinoid-1 (CB1) receptor. As such, compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine. The compounds are also useful for the treatment of eating disorders by inhibiting excessive food intake and the resulting obesity and complications associated therewith including left ventricular hypertropy. The compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction, as well as for the treatment of asthma, and cirrhosis of the liver.